Substitute thiophenes and uses thereof

Abstract

This invention relates to novel compounds having the structural formula (I) and to their pharmaceutical salts, compositions and methods of use. These novel compounds provide a treatment or prophylaxis of cancer.

1. A compound of formula (I) or a pharmaceutically-acceptable salt or in vivo-hydrolysable precursors thereof: 
       
         
           
           
               
               
           
         
       
       wherein:
 R 1  is an optionally substituted heterocyclyl; 
 R 2  is selected from H, optionally substituted C 1-6 alkyl, or optionally substituted heterocyclyl; 
 R 4  is selected from H, OH, optionally substituted carbocyclyl, optionally substituted heterocyclyl, or optionally substituted C 1-6 alkyl; 
 R 5  is selected from H, optionally substituted carbocyclyl, or optionally substituted C 1-6 alkyl. 
 
     
     
       2. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof as recited in  claim 1  wherein R 2 , R 4 , and R 5  have any of the meanings defined in  claim 1  and R 1  is an optionally substituted heterocyclyl wherein 1,2, or 3 substituents is/are independently selected from halogen, nitro, amino, cyano, trifluoromethyl, alkyl, alkenyl, alkynyl, haloalkyl, alkoxy, hydroxy, alkylhydroxy, carbonyl, —CH(OH)CH 3 , —CH 2 NH-alkyl-OH, alkyl-(OH)CH 3 , —CH 2 -phenyl-(OCH 3 ) 2 , —Oalkyl, —OCH 3 , —Ophenyl, —OCOalkyl, —NHCHO, —Nalkyl, —N-(alkyl)-CHO, —NH—CO-amino, —N-(alkyl)-CO-amino, —NH—COalkyl, —N-(alkyl)-COalkyl, -carboxy, -amidino, —CO-amino, —CO-alkyl, —CO 2 alkyl, mercapto, —Salkyl, —SCH 2 furanyl, —SO(alkyl), —SO 2 (alkyl), —SO 2 -amino, -alkylsulfonylamino, phenyl, anisole, dimethoxyphenyl, trimethoxyphenyl, halophenyl, cycloalkyl, heterocyclyl, -alkyl-NH-cycloalkyl, -alkyl-NH- heterocyclyl, -alkyl-NH-alkyl-OH, —C(═O)OC(CH 3 ) 3 , —N(CH 3 ) 2 , —N(CH 2 CH 3 ) 2,  -alkyl-NH- alkyl- heterocyclyl, -alkyl-aryl, -methyl-phenyl, alkyl-polycyclyl, alkyl-amino, alkyl-hydroxy, —CH 2 NH-alkyl-heterocyclyl, —CH 2 NHCH2CH(CH 3 ) 2 , vicinal —O(alkyl)O—, vicinal —OC(haloalkyl)O—, vicinal —CH 2 O(alkyl)O—, vicinal —S(alkyl)S— and —O(alkyl)S—. 
     
     
       3. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof as recited in  claim 1  wherein R 2 , R 4 , and R 5  have any of the meanings defined in  claim 1  and R 1  is an optionally substituted heterocyclyl wherein 1,2, or 3 substituents is/are independently selected from: —OH, C(═O)OC(CH 3 ) 3 , NH 2 , C 1-6 alkyl, methoxybenzene, or dimethoxy benezene. 
     
     
       4. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof as recited in  claim 1  wherein R 2 , R 4 , and R 5  have any of the meanings defined in  claim 1  and
 R 1  is a heterocyclyl wherein heterocyclyl is selected from piperdinyl, pyridinyl, pyrrolidinyl, pyrazinyl, azepanyl, azetidinyl, azabicyclozinyl, furanyl, thienyl. 
 
     
     
       5. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof as recited in  claim 1  wherein R 1 , R 4 , and R 5  have any of the meanings defined in  claim 1  and
 R 2  is H. 
 
     
     
       6. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof as recited in  claim 1  wherein R 1 , R 2 , and R 5  have any of the meanings defined in  claim 1  and
 R 4  is H. 
 
     
     
       7. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof as recited in  claim 1  wherein R 1 , R 2 , and R 4  have any of the meanings defined in  claim 1  and
 R 5  is H or an optionally substituted C 1-6 alkyl. 
 
     
     
       8. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof as recited in  claim 1  wherein R 1 , R 2 , and R 4  have any of the meanings defined in  claim 1  and
 R 5  is H or an optionally substituted C 1-6 alkyl wherein 1,2 or 3 substituents is/are independently selected from: NH 2 , NHCH 3 , N(CH 2 CH 3 ) 2 , N(CH 3 ) 2 , OCH3, OH, —C 1-6 alkyl, morpholino, piperidinyl, pyrrolodinyl. 
 
     
     
       9. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof as recited in  claim 1  wherein R 1 , R 2 , and R 4  have any of the meanings defined in  claim 1  and
 R 5  is H or an optionally substituted C 1-3 alkyl. 
 
     
     
       10. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof as recited in  claim 1  wherein R 1 , R 2 , and R 4  have any of the meanings defined in  claim 1  and
 R 5  is H or an optionally substituted C 1-3 alkyl wherein 1,2 or 3 substituents is/are independently selected from: NH 2 , NHCH 3 , N(CH 2 CH 3 ) 2 , N(CH 3 ) 2 , OCH3, OH, —C 1-6 alkyl, morpholino, piperidinyl, pyrrolodinyl. 
 
     
     
       11. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof, as recited in  claim 1  wherein:
 R 2  is H; 
 R 4  is H; 
 R 5  is H or an optionally substituted C 1-6 alkyl. 
 
     
     
       12. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof, as recited in  claim 1  wherein:
 R 1  is an optionally substituted heterocyclyl wherein the substituent is selected from one or more of the following: —NH 2 , C 1-6 alkyl, —C(═O)OC(CH 3 ) 3 , 
 R 2  is H; 
 R 4  is H; 
 R 5  is H or an optionally substituted C 1-6 alkyl wherein the substituent is selected from one or more of the following: —C 1-6 alkyl, —N(C 1-3 alkyl) 2 . 
 
     
     
       13. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof, as recited in  claim 1  wherein:
 R 1  is an optionally substituted heterocyclyl wherein the substituent is selected from one or more of the following: —NH 2 , C 1-6 alkyl, —C(═O)OC(CH 3 ) 3 , 
 R 2  is H; 
 R 4  is H; 
 R 5  is H or an optionally substituted C 1-3 alkyl wherein 1,2 or 3 substituents is/are independently selected from: NH 2 , NHCH 3 , N(CH 2 CH 3 ) 2 , N(CH 3 ) 2 , OCH3, OH, —C 1-6 alkyl, morpholino, piperidinyl, pyrrolodinyl. 
 
     
     
       14. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof, as recited in  claim 1  wherein:
 R 1  is a heterocyclyl; 
 R 2  is H; 
 R 4  is H; 
 R 5  is H or a C 1-6 alkyl. 
 
     
     
       15. A compound of formula (I) or a pharmaceutically-acceptable salt or an in vivo-hydrolysable precursor thereof, as recited in  claim 1  wherein:
 R 1  is a 6-membered heterocyclyl containing at least one N in the ring; 
 R 2  is H; 
 R 4  is H; 
 R 5  is a C 1-3 alkyl. 
 
     
     
       16. A compound of formula (I) or a pharmaceutically-acceptable salt thereof, as recited in  claim 1  selected from:
 tert-butyl 3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate; 
 2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide; 
 tert-butyl 3-{[(2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate; 
 2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-ylthiophene-3-carboxamide; 
 2[(aminocarbonyl]-N-[(3R)-azepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamide; 
 N-(3-[(4-aminopiperidin-1-yl)carbonyl]-5-{4-[2-(diethylamino)ethoxy]phenyl}-2-thienyl)urea; 
 2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-pyridin-3-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(1-methylpiperidin-4-yl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-1-methylazepan-3-yl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-[3-(hydroxymethyl)phenyl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-pyrrolidin-3-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-pyridin-3-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-1-methylpiperidin-3-yl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-{3-[2-(diethylamino)ethoxy]phenyl}-N-pyrrolidin-3-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-piperidin-3-ylmethyl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-pyrrolidin-3-yl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-piperidin-3-yl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(piperidin-4-ylmethyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-pyrrolidin-3-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-N-(1-ethylpiperidin-3-yl)-5-(4-methoxyphenyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-N-[(3S)-1-ethylazepan-3-yl]-5-(4-methoxyphenyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(3-hydroxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide; 
 tert-butyl(3S)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)pyrrolidine-1-carboxylate; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-piperidin-3-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-N-(1-benzylpiperidin-4-yl)-5-(4-methoxyphenyl)thiophene-3-carboxamide; 
 tert-butyl 3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate; 
 2-[(aminocarbonyl)amino]-5-[4-(2-piperidin-1-ylethoxy)phenyl]-N-(2-pyridin-4-ylethyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-[4-(2-piperidin-1-ylethoxy)phenyl]-N-(2-pyridin-4-ylethyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-N-azetidin-3-yl-5-(4-methoxyphenyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(2S)-pyrrolidin-2-ylmethyl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-pyridin-4-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-piperazin-1-ylethyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-piperidin-1-ylethyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-(2-pyridin-4-ylethyl)thiophene 3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-piperazin-1-ylethyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-pyridin-4-ylethyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-(2-pyridin-3-ylethyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-pyridin-3-ylethyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2,2,6,6-tetramethylpiperidin-4-yl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(2-methoxyphenyl)-N-piperidin-4-ylthiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(tetrahydrofuran-2-ylmethyl)thiophene-3-carboxamide; 
 tert-butyl(3R)-3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(pyridin-3-ylmethyl)thiophene-3-carboxamide; 
 tert-butyl 3-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)azetidine-1-carboxylate; 
 2-[(aminocarbynol)amino-5-(4-methoxyphenyl)-N-(pyridine-4-methyl)thiophene-3-carboximide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[2-(2-thienyl)ethyl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-thienylmethyl)thiophene-3-carboxamide; 
 N-[3-(1,4-diazepan-1-ylcarbonyl)-5-(4-methoxyphenyl)-2-thienyl]urea; 
 2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-(2-thienylmethyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-N-{2-[(2-furylmethyl)thio]ethyl}-5-(4-methoxyphenyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-hydroxyphenyl)-N-[2-(2-thienyl)ethyl]thiophene-3-carboxamide; 
 N-(3-[(4-aminopiperidin-1-yl)carbonyl]-5-{3-[2-(diethylamino)ethoxy]phenyl}-2-thienyl)urea; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(3R)-piperidin-3-ylmethyl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(1,2,3,4-tetrahydroquinolin-3-yl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-N-(1,3-benzodioxol-5-ylmethyl)-5-(4-methoxyphenyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-[(5-methyl-2-furyl)methyl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(pyridin-2-ylmethyl)thiophene-3-carboxamide; 
 tert-butyl 4-({[2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate; 
 2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-N-(2-pyridin-2-ylethyl)thiophene-3-carboxamide; 
 tert-butyl 4-({[2-[(aminocarbonyl)amino]-5-(4-methoxyphenyl)-3-thienyl]carbonyl}amino)piperidine-1-carboxylate; 
 2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-N-[(3R)-piperidin-3-yl]thiophene-3-carboxamide; 
 tert-butyl(3S)-3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate; 
 2-[(aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-{4-[2-(diethylamino)ethoxy]phenyl}thiophene-3-carboxamide; 
 tert-butyl(3R)-3-{[(2-[(aminocarbonyl)amino]-5-{4-[2-(diethylamino)ethoxy]phenyl}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate; 
 N-[3-{[(3S)-3-aminoazepan-1-yl]carbonyl}-5-(4-methoxyphenyl)-2-thienyl]urea; 
 5-{4-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide; 
 5-{3-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide; 
 5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide; 
 N-[(3S)-azepan-3-yl]-5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide; 
 5-{3-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide; 
 N-(2-aminoethyl)-5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide; 
 5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-3-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide; 
 5-(4-methoxyphenyl)-N-piperidin-4-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide; 
 tert-butyl 3-{[(5-{3-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate; 
 5-{4-[2-(diethylamino)ethoxy]phenyl}-N-piperidin-4-yl-2-{[(pyrazin-2-ylamino)carbonyl]amino}thiophene-3-carboxamide; 
 5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-N-[(3S)-pyrrolidin-3-yl]thiophene-3-carboxamide; 
 N-[3-(1,4-diazepan-1-ylcarbonyl)-5-(4-methoxyphenyl)-2-thienyl]-N′-pyrazin-2-ylurea; 
 N-[3-[(3-aminopyrrolidin-1-yl)carbonyl]-5-(4-methoxyphenyl)-2-thienyl]-N′-pyrazin-2-ylurea; 
 tert-butyl 4-{[(5-(4-methoxyphenyl)-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate; 
 tert-butyl 3-{[(5-{4-[2-(diethylamino)ethoxy]phenyl}-2-{[(pyrazin-2-ylamino)carbonyl]amino}-3-thienyl)carbonyl]amino}piperidine-1-carboxylate; 
 5-[4-(2-diethylamino-ethoxy)-phenyl]-2-(3-hydroxy-urea)-thiophene-3-carboxylic acid-(S)-piperidin-3-ylamide; 
 2-[(aminocarbonyl)amino]-N-[(3S)-azepan-3-yl]-5-(3-methoxyphenyl)thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(2-hydroxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-(3-methoxyphenyl)-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide; 
 2-[(aminocarbonyl)amino]-5-[2-(benzyloxy)phenyl]-N-[(3S)-piperidin-3-yl]thiophene-3-carboxamide. 
 
     
     
       17. A pharmaceutical composition comprising a compound of formula (I) or a pharmaceutically acceptable salt thereof as defined in  claim 1  together with at least one pharmaceutically acceptable carrier, diluent or excipient.